Method of production of ceramics

ABSTRACT

Spherical-shape ceramics obtained by dropping starting ceramics into a low temperature medium or composite spherical-shape ceramics having a composite layer obtained by applying a hydrothermal treatment thereto.

TECHNICAL FIELD

The present invention relates to a process for producing ceramics, morespecifically relates to a process for producing porous ceramics suitablefor use as a bone filler or a DDS carrier. The present invention furtherrelates to composite spherical-shape ceramics suitable for use as amedical or dental bone filler or bone cement or other bioceramicmaterial or various resorbable carriers etc.

BACKGROUND ART

In the past, as ceramics having superior biocompatibility, in the fieldof bone fillers and bone cement, calcium phosphate has been broadlyused. The forms at the time of use have mostly been splinter-powder(break to powder), blocks, porous substances, self-setting cements, etc.In particular, in bone fillers, some splinter-powder (break to powder)and blocks have been commercialized.

As an example of application of calcium phosphate, recently attentionhas been made to the use for DDS carriers. For example, JapaneseUnexamined Patent Publication (Kokai) No. 60-106459 discloses a processfor producing a sustained drug release type carrier comprising coatingcombustible beads with calcium phosphate and then sintering them tocause the combustible beads to burn away and leave hollow beads ofcalcium phosphate, then filling a drug into the hollow portions.Further, Japanese Unexamined Patent Publication (Kokai) No. 59-101145discloses a process for producing a carrier having a similar effect byimpregnating a drug into porous calcium phosphate having open pores.

However, in the above processes, the production steps, such as theinjection of the drug into the hollow beads, becomes complicated.Further, it is difficult to control the rate of sustained release of thedrug. In the latter process as well, similarly there is a concern overproblems such as the complexity of the production steps and thedifficulty of control of the rate of sustained release.

On the other hand, spherical-shape calcium phosphate is used as a columnfiller for liquid chromatography. The general production process is aspray drying granulation method. The spray drying granulation method isgenerally used for the production of particles having a particle size of100 μm or less. An extremely large-sized apparatus is required whenproducing larger particles. Further, as a process for producingspherical-shape calcium phosphate having a size of 100 μm or more,Japanese Unexamined Patent Publication (Kokai) No. 64-75030 discloses aprocess comprising injecting a ceramics slurry into an oil phase to forma water-in-oil emulsion, then injecting this again into a water phase tosolidify the oil phase, followed by sintering to burn off the oil phase,whereby spherical-shape calcium phosphate is obtained.

However, for use as a bone filler, particles having a size of 100 μm ormore are desirable. Capital investment is required for producing this bythe spray drying granulation method, and therefore, the costs areincreased. Further, in the process disclosed in Japanese UnexaminedPatent Publication (Kokai) No. 64-75030, production steps for adjustingthe oil phase etc. become necessary, and therefore, there are againconcerns of increased cost.

An application for DDS requires a superior drug carrying property,biocompatibility, sustained drug release, and biodegrarative. Calciumphosphate is superior in biocompatibility and resorption in the livingbody or organism. In the past, considerable research went into itsapplication for DDS, but nothing has been commercialized yet. One of thereasons is that, since it is ceramics, it is hard to process. Porosityhas to be imparted in order to carry a drug, but it is difficult tochange conditions such as the size, strength, distribution of pores,etc. Further, from the viewpoint of the rate of filling in the diseasedlocation or operability, it is desirable that DDS carriers and bonefillers be spherical. Since it is extremely difficult to processceramics into spheres, this has not yet been commercialized.

Spherical-shape particles have applications in a broad range of fieldssuch as processing powders and carrying catalysts, so that thespherical-shape particles which can be supplied to these fields, it isparticularly preferable or sought to produce them in a manner enablingthe particle size to be changed in depending upon the order and toenable the particles themselves to functionally carry varioussubstances.

In the medical field, the properties of the particles themselves havecome under focus along with the development of drug delivery systemswhich use particles to carry a drug and effectively release the drug atthe desired location in the organism.

Further, in biomaterials as well, calcium phosphate is being broadlyused in the fields of bone fillers and bone cement as ceramics superiorin biocompatibility. The shapes at the time of use are mostlysplinter-powder (break to power), blocks, porous substances,self-setting cement, etc. In particular, in bone fillers, somesplinter-powder (break to powder) or blocks have been commercialized.

Japanese Unexamined Patent Publication (Kokai) Nos. 3-131580 and1-314572 disclose processes of preparation of a porous block of calciumphosphate ceramics. In these processes, it is necessary to shape theblock at the time of surgery to match the shape of the bone loss.Further, the implanted block member is often scattered or ejected fromthe organism before the fusion with the newly grown bone.

To overcome this problem, that is, to cause the granules to fix witheach other, Japanese Unexamined Patent Publication (Kokai) Nos.60-256460 and 60-256461 attempt to use a fibrin paste as a glue.However, a fibrin paste is produced from human blood, therefore had therisk of infection by hepatitis, AIDS, etc.

Further, Japanese Unexamined Patent Publication (Kokai) No. 59-88351 andNo. 59-182263 disclose processes for producing a bone repair cementhaving α-tricalcium phosphate or tetracalcium phosphate as its mainingredient. In these processes, the cement cures at the bone lossportion, then fixes to it densely, so osteoblasts and other tissue andcells will not enter the inside of the filler such as with a porousblock. Therefore, the bone substitution ability of a calcium phosphateporous block is superior.

The conventional granular bone filler or porous calcium phosphate blockoften scatters before fusion with the newly grown bone when implanted ina bone loss portion. Further, the bone cement is inferior in bonesubstitution capability compared with a porous calcium phosphate bonefiller due to the fact that it fixes densely after curing. Therefore, agranular bone filler or porous calcium phosphate block capable ofachieving anchoring or preventing scattering at the bone loss portion ispreferred. No bone filler having both the functions of a bone filler andbone cement has yet been commercialized.

DISCLOSURE OF THE INVENTION

Accordingly, an object of the present invention is to provide atechnique for easily processing a hard-to-process calcium phosphateceramics into a spherical shape, whereby an effective means of treatmentof cancer or bone tumors by impregnation of a drug and administration tothe diseased portion is provided, since the spherical-shape ceramics haspores and a resorption in the organism optimal for DDS.

Another object of the present invention is to enable the simple and easyproduction of spherical-shape ceramics having a functional compositelayer having a porous inside and having an outer periphery withdifferent physical properties from the inside, more particularly, toprovide a bone filler which enables fusion with newly grown bone or bonesubstitution action quickly in a natural manner, without scattering,when filled in a bone loss portion and a process of production of thesame.

In accordance with the present invention, there is provided a processfor producing ceramics by dropping starting ceramics into a lowtemperature medium, followed by freeze drying and, then sintering.

In accordance with the present invention, there is further providedcomposite spherical-shape ceramics having a composite layer obtained bydropping a starting material powder into a low temperature mediumapplying a hydrothermal treatment to the resultant spherical-shapeceramics.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will now be explained in detail with reference tothe drawings.

FIGS. 1(a) and 1(b) are scanning-type electron micrographs of thesurface of porous ceramics powder shown in Example I-2 (100x and 1000x,respectively).

FIGS. 2(a) and 2(b) are scanning-type electron micrographs of the slicedcross-section of porous ceramics powder shown in Example I-2 (100x and1000x, respectively).

FIGS. 3(a), 3(b), 3(c), 3(d), 3(e), 3(f), 3(g), 3(h), 3(i), and 3(j) arescanning-type electron micrographs showing the mode of dissolution alongwith time of the porous ceramics shown in Example I-4 in ion exchangewater.

FIGS. 4(a) and 4(b) are scanning-type electron micrographs of the frozensliced cross-section of porous ceramics shown in Example I-5 (1000x and3000x, respectively).

FIG. 5 is a graph of the results of Example I-6.

FIGS. 6(a) and 6(b) are scanning-type electron micrographs afterimmersion in a refrigerant in the production process of thespherical-shape ceramics of the present invention (150x and 1000x,respectively).

FIGS. 7(a) and 7(b) are scanning-type electron micrographs after thehydrothermal treatment in the process of production of thespherical-shape ceramics of the present invention (150x and 1000x,respectively).

FIGS. 8(a) and 8(b) are scanning-type electron micrographs after cementcoating in the process of production of the spherical-shape ceramics ofthe present invention (150x and 1000x, respectively).

BEST MODE FOR CARRYING OUT THE INVENTION

A first embodiment of the present invention will now be explained.

Calcium phosphate synthesized by a known synthesis method, preferablywet synthesis or dry synthesis, preferably hydroxyapatite, tricalciumphosphate, calcium dihydrogenphosphate, tetracalcium phosphate,octacalcium phosphate, calcium phosphate glass, or mixtures thereofcalcium phosphates, more preferably tricalcium phosphate, is made into apowder, preferably not more than 100 microns, using a pulverizer orspray dryer etc. Into this powder is added, stirred, and mixed a binderslurry, preferably, an aqueous solution of one or more of awater-soluble cellulose derivative, polyvinyl alcohol, polyacrylic acid,polyacrylamide, polyvinyl pyrrolidone, polyethylene glycol, and starch,more preferably a 3 to 15% by weight aqueous solution of polyvinylalcohol or polyethylene glycol in an amount of 1 to 5 times, preferably2 to 4 times, of the weight of the powder. At this time, a similarresult can be obtained even if using a 10 to 50% by weight slurry ofcalcium phosphate other than the powder.

As the ceramics in the present invention, in addition to theabove-mentioned calcium phosphate ceramics, alumina, zirconia, carbon,etc. may be mentioned.

The above-mentioned binders are merely examples. In addition, additivesmay sometimes be added depending upon the mode of use etc., for example,a glycol may be added as a stabilizing agent. Further, if not a porousstate, the binder may not be necessary.

The calcium phosphate slurry obtained containing a binder is filled intoa cylinder and is dropped from a thin tube attached to the front end ofthe cylinder, preferably having an inner diameter of 0.3 to 2 mm, into alow temperature refrigerant solution prepared in advance and having atemperature of about −10° C. or less, preferably, liquid nitrogen,liquid helium, acetone+dry ice, methanol+dry ice, or ethyl ether+dryice.

The dropped calcium phosphate slurry containing the binder becomesspherical shape during its fall and at the surface of the liquidnitrogen and can be frozen, while maintaining the spherical shape.

The frozen slurry obtained is freeze-dried so as not to thaw and tocompletely remove the moisture. The spherical-shape calcium phosphatethus obtained is sintered using an electric furnace at 800° C. to 1500°C., preferably 1000° C. to 1400° C., to obtain the spherical-shapeceramics.

The diameter of the ceramics powder obtained by this production processis 0.01 to 10 mm, but can be adjusted in various ways by the mode ofcontact such as the dropping conditions.

In the present invention, it is sufficient to bring the ceramicssolution into contact with a low temperature refrigerant. Various modesof contact are possible, but other than the dropping, spraying by anatomizer such as a spray dryer, pressurized spraying by a spray, contactwith a container in by injection, pouring, and other means ofintroduction into a container, etc. may be mentioned.

The spherical-shape ceramics has fine pores formed at the time ofevaporation of the binder over the spheres as a whole. A drug etc. maybe impregnated into the ceramics from these pores. Further, the diameterof the pores may be varied by the content of the binder. Further, sincethe pores can be plugged by a known calcium phosphate cement or othersynthetic resin etc., control of the rate of sustained release ispossible.

Due to the uniform porosity, the sustainability of the sustained releasein the orgnism is, for example, units of several days or several weeksin the body fluids, more specifically for one week to three weeks. Asimilar sustainability can be obtained in the body tissue as well.

Therefore, by filling this spherical-shape ceramics into a portion ofbone loss, since the pores, one of the features of this spherical-shapeceramics, do not block the flow of blood, it is possible to quicklyregenerate the bone. Further, the effect can be enhanced further byimpregnating the pores with bone-growth factors, collagen, antibiotics,and other drugs.

The present invention, in addition to the above, may be used as a mainmaterial or additive etc. for various products such as orallyadministered drugs, processed foods, beverages, various adsorptioncolumn materials, cosmetics, dentifrices, fumigants, air fresheners anddeodorizing agents, bath additives, facial cleansers, shampoos, andother toiletries, fibers having adsorption or other functions or papermaterials and other fields requiring adsorption and sustained release ofthe carried substances.

In this above way, a good sustained release drug can be obtained bycarrying various drugs. Due to the superior sustained release, forexample, penicillin type antibiotics, tetracycline type antibiotics, theanticancer drugs 5FU, carboplatin, cisplatin, etc. are preferably used.

The specific production process of composite spherical-shape ceramicsaccording to the second aspect of the present invention comprises mixinga binder into a high purity calcium phosphate powder obtained by aknown. synthetic method, preferably wet synthesis and dry synthesis,preferably a hydroxyapatite, tricalcium phosphate, or tetracalciumphosphate, then shape the mixture by any method and sinter it at atemperature of 800 to 1500° C. to obtain a calcium phosphate ceramicssuperior in biocompatibility. As the method of shaping, a monoaxialpress, rubber press, etc. may be used for easy shaping. Further, bymixing a burn-off substance in the binder, it is possible to make theceramics porous after sintering. Porous ceramics facilitate the entry ofosteoblasts and other tissue in the organism and a bone regeneratingcapability to be exhibited more suitably, when implanted in a bone lossportion. However, since the dynamic strength is poor, it is necessary topay close attention at the time of use.

The porous or dense calcium phosphate ceramics obtained, and a suitableamount of ion exchange water are placed in a heat resistant sterilebottle and heated in a sealed atmosphere at 80° C. to 150° C.,preferably 100° C. to 120° C., for at least 30 minutes, preferably 12 to24 hours to cause high purity calcium phosphate crystal to precipitateon the surface of the ceramics (hereinafter this technique is called“hydrothermal treatment”). The crystal is comprised of the phosphoricacid and calcium eluted from the surface of the sintered productreprecipitating on the surface of the ceramics. Therefore, an extremelyhigh purity calcium phosphate crystal precipitates over the entiresurface of the ceramics. The particles of ceramics grow by the sinteringand the specific surface area rapidly drops. However, by using the aboveprocess to cause crystals to precipitate on the surface, the specificsurface area can be restored to a certain extent again. By increasingthe specific surface area, it is possible to obtain an anchoring effectin the organism even if used as a bone filler in this state.

The hydrothermal treatment in the present invention may be performed bycausing crystal to precipitate in steam using an autoclave in additionto the above technique. More specifically, this consists of heating themixture under a sealed steam atmosphere in an autoclave at 80° C. to150° C., preferably 100° C. to 120° C., for at least 30 minutes,preferably 12 to 24 hours so as to cause high purity calcium phosphatecrystal to precipitate on the surface of the ceramics. Further, in theprocess using a heat resistant sterilize bottle or the process using anautoclave, it is possible to reduce the hydrothermal treatment time andcontrol the precipitated layer by using an aqueous solution forimpregnated with the ceramics and an aqueous solution containingcalcium, phosphate, or other ions in a steam atmosphere.

In this hydrothermal treatment, the width of the precipitated layer iscontrolled by the treatment time, amount of pressure, pressurizingtemperature, treatment atmosphere, etc. Specifically, it may be suitablyselected depending upon the application such as the bone filler, DDScarrier, dental root canal filler, ceramics adsorbent, columnchromatography filler, or other application.

The coating method of a cement on the surface of a bone filler, withoutimpairing, the setting (or curing) function, to enhance the anchoringeffect is explained below. The calcium phosphate ceramics with crystalprecipitated on the surface thereof is mixed with a bone cement whichcures by kneading with water and a setting (or curing) solution. As thebone cement, α-tricalcium phosphate, tetracalcium phosphate, octacalciumphosphate, calcium sulfate, or any mixture thereof is preferable as thecement.

Further, the present invention is not limited in biomaterials. Any fineparticles having the composite layer, in particular porous fineparticles, which can be made to carry various substances in the porousportions are particularly preferred.

After mixing, a suitable amount of ion exchange water is added andquickly kneaded. The cement is instantaneously frozen in liquidnitrogen, liquid helium, or another super-low temperature medium orsuper-low temperature atmosphere before the cement completely sets (orcures). A bone cement has a large specific surface area. The crystalgrowth starts by a hydrolysis reaction when moisture adheres to thecement surface. By mixing and kneading this with a cement material, thebone cement in the intervals of the crystals precipitated on the surfaceof the ceramics can stop the crystal growth due to the setting by theinstantaneous freezing. The instantaneously frozen bone cement and bonefiller are then freeze-dried. The freeze-drying can completely removethe moisture while maintaining the specific surface area of the cementto a certain extent. Therefore, it is possible to separate the driedproduct obtained into the bone filler and cement, then cause it tofunction as cement again.

Bone cement is taken into the intervals of the crystal reprecipitated onthe surface of the bone filler. The bone cement taken in secures thespecific surface area required for setting due to the freeze-drying.Therefore, the bone filler according to the present invention is a bonefiller coated on the surface thereof with a setting type bone cement.When implanted in a bone loss portion, it can bond with the portion bythe setting action of the surface and effectively prevent the bonefiller from scattering after implantation. Further, by making the coreceramics porous, there is the same bone substitution ability as agranular porous filler.

As explained above, as the drug carried, a broad range of drugs can beused. Further, since the surface is treated by reprecipitation, the rateof dissolution in the organism is adjusted, therefore the functionbecomes extremely marked.

A good sustained release drug is obtained by carrying various drugs. Dueto the superior sustained release, for example, penicillin typeantibiotics, tetracycline type antibiotics, the anticancer drugs 5FU,carboplatin, cisplatin, acrarubicin hydrochloride, daunorubicinhydrochloride, neocartinostatin, acutinomycin D, pepromycin sulfate,piralbicin hydrochloride, doxorubicin hydrochloride, bleomycinhydrochloride, bleomycin sulfate, mitomycin, and other drugs may besuitably used.

In the second embodiment of the present invention as well, in additionto the above, the present invention may be used as a main material orsubstrate etc. for various products such as orally administered drugs,processed foods, beverages, various adsorption column materials,cosmetics, dentifrices, fumigants, air fresheners and deodorizingagents, bath additives, facial cleansers, shampoos, and othertoiletries, fibers having adsorption or other functions or papermaterials and other fields requiring adsorption and sustained release ofthe carried substances.

EXAMPLES

The present invention will be explained in more detail with reference toExamples, but the present invention is of course not limited to theseExamples in scope.

Example I-1

1 g of calcium phosphate powder (#400 mesh or less) having Ca/P=1.48synthesized by a known wet synthesis method was mixed into 3 g of a 10%by weight aqueous solution of polyvinyl alcohol, then 0.5 g of ionexchange water was added and the mixture further mixed and stirred. 10ml of the slurry obtained was filled into a thermosyringe and a 24 Gneedle (inner diameter 0.47 mm) was used to drop it into liquidnitrogen. The frozen product obtained was dried using a vacuum freezedryer, then was sintered at 1400° C. for 5 hours to obtain 0.9 g ofspherical-shape ceramics. The spherical-shape frozen product obtainedhas a diameter of 0.8 to 1.2 mm. Powder X-ray measurement confirmed thatthe spherical-shape ceramics was a single phase of α-tricalciumphosphate.

Example I-2

The spherical ceramics prepared in Example I-1 was observed by ascanning-type electron microscope (SEM). The sample was observed by twotypes of methods: the surface of the sample and the sliced section ofthe sample. As a result, the surface of the sample was observed to havepores of 1 to 4 μm distributed over its entire surface. Further, the SEMimage of the sliced section showed that there were pores of 100 to 200μm inside the spherical-shape ceramics. It was confirmed that there wasa mozaic structure of calcium phosphate around it. (See FIGS. 1(a) and1(b) and FIGS. 2(a) and 2(b).)

Example I-3

The spherical ceramics prepared in Example I-1 was immersed in red ink,then deaerated under vacuum for about 10 minutes. This was returned toordinary pressure, then the excess ink was wiped off and the sampledried by freeze-drying in vacuum. The sample was sliced at its centerportion, whereupon it was confirmed that the red ink had penetrated tothe inside of the ceramics. Therefore, it is possible to easilyimpregnate a drug by just a short period of vacuum deaeration.

Example I-4

The spherical-shape porous ceramics prepared in Example I-1 was immersedin 50 ml of ion exchange water for 1 hour, 1 day, 3 days, 7 days, and 14days and the form of dissolution was observed over time by ascanning-type electron microscope. The obtained electron micrographs areshown in FIGS. 3(a) (1 hour, 500x), 3(b) (1 hour, 1000x), 3(c) (1 day,500x), 3(d) (1 day, 1000x), 3(e) (3 days, 500x), 3(f) (3 days, 1000x),3(g) (7 days, 500x), 3(h) (7 days, 1000x), 3(i) (14 days, 500x), and3(j) (14 days, 1000x). The sample was a spherical-shape porous ceramicsfor a drug carrier superior in resorption in the body.

As a result, it was confirmed that the spherical-shape porous ceramicsquickly dissolved and the state of dissolution occurred with units ofclump of grain peeling off in a plate shape. A similar trend may be seenin the body as well. This material was shown to be a material which isfinally completely resorbed while releasing the drug.

Example I-5

The spherical-shape porous ceramics prepared in Example I-1 was immersedin a dispersion of fine hydroxyapatite particles and subjected toultrasonic waves, while being vacuum deaerated. Then, the sample wasfrozen and sliced and observed under a scanning-type electronmicroscope.

1 g of calcium phosphate powder (#400 mesh or less) having Ca/P=1.48synthesized by a known wet synthesis method was mixed into 3 g of a 10%by weight aqueous solution of polyvinyl alcohol, then 0.5 g of ionexchange water was added and the mixture further mixed and stirred. 10ml of the slurry obtained was filled into a thermosyringe and a 24 Gneedle (inner diameter 0.47 mm) was used to drop it into liquidnitrogen. The frozen product obtained was dried using a vacuum freezedryer, then was sintered at 1400° C. for 5 hours to obtain 0.9 g ofspherical-shape ceramics. The spherical-shape frozen product obtainedhas a diameter of 0.8 to 1.2 mm. (See FIGS. 6(a) and 6(b).)

Example I-6

As a simulation experiment for confirming the sustained drug releaseeffect, 10% by weight of fine hydroxyapatite particles was mixed into a10 mM aqueous Methyl orange solution and stirred well. This was filledinto the fine pores of the spherical-shape porous ceramics by the methodshown in Example I-5. 0.2 g of the sample filled in the fine pores wasintroduced into 200 ml of ion exchange water, then the immersionsolution was taken after a predetermined time and the amount of elutionof Methyl Orange was compared by the absorbance by an ultravioletspectrophotometer. As a control, spherical-shape porous ceramics withoutthe fine pores filled immersed in a 10 mM aqueous Methyl Orange solutionwas used.

As a result, it was found that the sample having the filled fine porescarried about three times the amount of Methyl Orange compared with asample not filled. Further, as a result of the sustained release, theMethyl Orange could be released over an approximately 10 times longerperiod. The possibility of obtaining excellent therapeutic effects byreplacing the Methyl Orange with various types of antibiotics orantitumor preparations was suggested (see FIG. 5).

Example II-1

1 g of calcium phosphate powder (#400 mesh or less) having a Ca/P=1.48synthesized by a known wet synthesis method was mixed into 3 g of a 10%by weight aqueous solution of polyvinyl alcohol, then 0.5 g of ionexchange water was added and the mixture further mixed and stirred. 10ml of the slurry obtained was filled into a thermosyringe and a 24 Gneedle (inner diameter 0.47 mm) was used to drop it into liquidnitrogen. The frozen product obtained was dried using a vacuum freezedryer, then this was sintered at 1400° C. for 5 hours to obtain 0.9 g ofspherical-shape ceramics. The spherical-shape ceramics obtained had adiameter of 0.8 to 1.2 mm. (See FIGS. 6(a) and 6(b).)

0.9 g of the spherical-shape ceramics obtained was inserted into a heatresistant sterile bottle, then 50 ml of ion exchange water was added andthe bottle corked. This was placed in a 120° C. incubator for 1 hour tomake calcium phosphate crystal precipitate on the surface of thespherical-shape ceramics. This was dried in the incubator, then thesurface condition was observed by a scanning-type electron microscope,whereupon it was confirmed that 10 to 20 μm calcium phosphate crystalswere distributed over the entire surface. (see FIG. 7(a) and 7(b).)

Example II-2

Spherical-shape ceramics on the surface of which calcium phosphatecrystal was precipitated, prepared in Example II-1, and calcium sulfatepowder were mixed and then a suitable quantity of ion exchange water wasadded to create a cement-like state. This was kneaded for 1 minute, thenthe cement was filled into an eggplant-shaped flask which was thenimmersed in liquid nitrogen to instantaneously freeze the cement. Then,this was quickly dried using a freeze dryer. The dried sample was passedthrough a rated sieve #100 to remove the surplus deposited calciumsulfate to coat calcium sulfate cement on the surface and obtain a bonefiller. (See FIGS. 8(a) and 8(b).)

Example II-3

To investigate the state of curing of the bone filler prepared inExample II-2, a hole of a diameter of about 4 mm was bored into the ribof a hog and the bone filler was filled in the hole. After about 1 hourafter filling, the bone filler completely set and it became impossibleto withdraw the bone filler from the hole. This experiment confirmed thelow possibility of the product of the present invention detaching fromthe diseased portion when filled in a portion of bone loss.

INDUSTRIAL APPLICABILITY

As explained above, according to the present invention, it is possibleto produce ceramics freely controlled in particle size and pore sizesimply and in a short time. Therefore, when used as a bone filler, thereis the effect of promoting bone regeneration, without blocking the flowof blood in the bone. Further, by impregnating a drug in the resorbableceramics, an ideal sustained drug release carrier is obtained.

According to the present invention, by coating a ceramic cement on thesurface of ceramics with a superior biocompatibility, the cement sets bya hydrolysis reaction when implanted at the bone loss portion andanchors the ceramics sintered granules in the bone loss portion.Therefore, while past granular bone fillers had suffered from theproblem of scattering from the bone loss portion, this problem has beensolved by the present invention.

What is claimed is:
 1. A process for producing porous spherically-shapedbio-ceramics comprising dropping a starting material for ceramics into alow temperature medium from a thin tube having an inner diameter rangingfrom about 0.3 to 2 mm, followed by freeze drying in the medium and thensintering the same, wherein the starting material is obtained by adding,to a calcium phosphate in the form of a powder having a size of not morethan 100 μm, a 3 to 15% by weight aqueous solution of a binder in anamount of 2 to 4 times the weight of the powder.
 2. A process forproducing porous spherically-shaped bio-ceramics as claimed in claim l,wherein the calcium phosphate is hydroxyapatite, tricalcium phosphate,calcium dihydrogenphosphate, tetracalcium phosphate, octacalciumphosphate, or a mixture thereof.
 3. A sustained drug release productobtained by forming the porous spherical-shape bio-ceramics obtainedaccording to claim 1 or 2, wherein the pores are impregnated with adrug.
 4. A sustained drug release product as claimed in claim 3,wherein, after the drug is impregnated into the porous bio-ceramics, theimpregnated parts are plugged by said bio-ceramics, whereby thesustained release time of the drug is controlled.
 5. A process forproducing porous spherically-shaped bio-ceramics comprising: bringing astarting material for bio-ceramics into contact with a low temperaturemedium by dropping the starting material into the low temperature mediumfrom a thin tube having an inner diameter ranging from about 0.3 to 2mm, wherein the starting material is obtained by adding, to a calciumphosphate in the form of a powder having a size of not more than 100 μm,a 3 to 15% by weight aqueous solution of a binder in an amount of 2 to 4times the weight of the powder, followed by freeze drying in the mediumto form a freeze dried product and; thereafter sintering the resultantfreeze dried product.
 6. A process for producing porousspherically-shaped bio-ceramics as claimed in claim 5, wherein thecalcium phosphate is hydroxyapatite, tricalcium phosphate, calciumdihydrogenphosphate, tetracalcium phosphate, octacalcium phosphate, or amixture thereof.
 7. A process for producing a sustained drug releaseproduct comprising impregnating the pores of the porous spherical-shapebio-ceramics obtained according to claim 1 or 2 with a drug.
 8. Aprocess as claimed in claim 7, wherein, after the drug is impregnatedinto the porous bio-ceramics, the impregnated parts are plugged by saidbio-ceramics, whereby the sustained release time of the drug iscontrolled.
 9. A process as claimed in claim 1, wherein the binderslurry is an aqueous solution of one or more of a water-solublecellulose derivative, polyvinyl alcohol, polyacrylic acid,polyacrylamide, polyvinyl pyrrolidone, polyethylene glycol, and starch.10. A filler for regenerating body tissue comprising porousspherically-shaped bio-ceramics obtained by a process according toclaim
 1. 11. A method for regenerating body tissue comprisingintroducing into areas where body regeneration is desired porousspherically-shaped bio-ceramics obtained by a process according toclaim
 1. 12. A process for producing porous spherically-shapedbio-ceramics as claimed in claim 1, wherein the porousspherically-shaped bio-ceramics each have a diameter ranging from about0.01 to about 10 mm.
 13. A process for producing a sustained drugrelease product according to claim 1 or 5 wherein the low temperaturemedium is liquid nitrogen.